A. Technical Background.
1. Drugs.
A drug is broadly defined as a chemical agent or medicinal substance that therapeutically affects the living processes of a patient. To perform its characteristic therapeutic activity, a therapeutic amount of a drug compound must be made bioavailable, i.e., it must be able to get to its site of action in the patient, via the blood stream, in the case of an oral or parenteral drug formulation. With respect to oral drug formulations (e.g., tablets, caplets, and capsules), a therapeutic amount of the drug must be first released from the dosage form over a given time in the gut, and, must be solubilized and absorbed in the gastrointestinal tract. After absorption, the active drug compound is metabolized, passes through the liver, and then it (and/or one or more of its metabolites) enters the general circulatory system towards the site of action. Thus, proper drug release from the dosage form, and solubilization of the active drug compound in the GI tract, are the critical first steps in the development of oral drug therapies.
The present invention relates to drug delivery systems that utilize liquid crystal structures and other means to dissolve and control the rate of dissolution of drug compounds, e.g., cyclosporine and nifedipine, that are poorly soluble in the gastrointestinal tract.
Medicinal substances which can be used in the present invention are varied and include, but are not limited to, antitussives, antihistamines, decongestants, alkaloids, mineral supplements, laxatives, vitamins, antacids, ion exchange resins, anti-cholesterolemics, anti-lipid agents, antiarrhythmics, antipyretics, analgesics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infectives, psycho-tropics, antimanics, stimulants, gastrointestinal agents, sedatives, antidiarrheal preparations, anti-anginal drugs, vasodilators, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, anti-uricemic drugs and mixtures thereof. Popular H.sub.2 -antagonists which are contemplated for use in the present invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifentdine, roxatidine, pisatidine and aceroxatidine. Analgesics include aspirin, acetaminophen, and acetaminophen plus caffeine, Ibuprofen. Other preferred active drugs for use in this invention include anti-diarrheals such as immodium AD. Also contemplated for use herein are anxiolytics such as Xanax; antipsychotics such as clozaril and Haldol; non-steroidal anti-inflammatories (NSAIDs) such as Voltaren and Lodine; anti-histamines such as terfenadine, Hismanal, Relafen, and Tavist; antiemtics such as Kytril and Cesamet; bronchodilators such as Bentolin, Proventil; antidepressants such as Prozac, Zoloft, Paxil and Buspar; antimigraines such as Imigran, ACE-inhibitors such as Vasotec, Capoten and Zestril; Anti-Alzheimers agents, such as Nicergoline; and Ca.sup.H -Antagonists such as Procardia, Adalat, and Calan, and salts thereof.
Especially preferred drugs for use in this invention are the immunosuppressants, e.g., the cyclosporins, and calcium antagonists, e.g., nifedipine and Ditiazem HCL. As discussed below, the present invention can be used for both hydrophilic and lipophilic drugs.
2. Cyclosporine, Nifedipine and Diltiazem.HCl.
The cyclosporins comprise class of structurally distinctive, cyclic, poly-N-methylated endecapeptides, possessing pharmacological activity, including, immunosuppressive, anti-inflammatory and/or anti-parasitic activity. Cyclosporine, also known as Cyclosporin A (see chemical structure shown below), was one of the first Cyclosporins to be isolated. See U.S. Pat. No. 5,342,625 to Birgit et al. Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids, and is produced in nature as a metabolite by the fungus species Beauveria nivea. See PHYSICIAN'S DESK REFERENCE, 51.sup.st Ed. (1997), p. 2405.
The chemical structure of cyclosporine is: ##STR1##
The present invention is intended to cover compositions of and methods employing the use of the cyclosporin class, which can be described as a group of nonpolar cyclic oligopeptides with immunosuppresant activity. This include Cyclosporins A, B, C, D and G. Cyclosporins are practically water-insoluble substances formed from neutral, hydrophobic amino acids. As a consequence of their high molecular weight (over 1000), poor water solubility, the cyclosporins are absorbed only to an insignificant extent from the gastrointestinal tract when administered orally. See U.S. Pat. No. 5,430,017 to Antalne et al. After oral administration, the bioavailability of cyclosporine or cyclosporin A is markedly poor and variable due to factors that include its poor solubility in aqueous gastrointestinal fluids, its high lipophilicity, as well as other factors such as impaired bile flow and fat content in the diet. See Chang et al., Clinical Pharmacology & Therapeutics, Vol. 59, No. 3 (March 1996).
Cyclosporine dosing is variable and depends on the type of organ transplanted. Generally, it about 7, 8 and 9 mg/kg of body weight, divided into two doses, for the heart, liver, renal (kidney), respectively. Cyclosporine has a biphasic terminal half-life of about 8.4 hours. Cyclosporine forms a solid solution with Vitamin E TPGS.
Nifedipine, or 3,5-pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester (see chemical structure shown below), is a potent peripheral vasodilator. About 90% of an oral dose of nifedipine is absorbed, but its bioavailability is 65% to 70%, and there is significant first pass metabolism. Greater than 10% of the drug is bound to plasma protein, and is metabolized to inactive metabolites, probably by the liver. Most of the inactive metabolites are excreted. The half-life is two to six hours.
The chemical structure of nifedipine is: ##STR2##
Nifedipine is practically insoluble in water. Its current dosage forms include 10 and 20 mg capsules. It is dosed three to four times a day, and doses exceeding 180 mg a day are not recommended. Nifedipine side effects of overdosing include pronounced hypotension requiring cardiovascular support.
For these reasons, Nifedipine is a good candidate for both enhanced solubility systems, and/or for use in a controlled release device which can effectively deliver a one to two per day dose. Nifedipine forms a solid solution with Vitamin E TPGS.
Diltiazem Hydrochloride, or benzothiazepin-4(5H)-one, 3-(acetyloxy)-52-(dimethylamino)ethyl!-2,3dihydro-2(4-methoxyphenyl)-, (+)-cis-, monohydrochloride (see chemical structure below), is a potent coronary vasodilator. Diltiazem-HCl is freely soluble in water. It is 80% absorbed orally, but only 40 to 60% of an oral dose reaches the systemic circulation because of first-pass metabolism.
The chemical structure of diltiazem hydrochloride is: ##STR3##
Diltiazem.HCl is metabolized extensively to several metabolites, some of which have weak coronary vasodilator activity. Less than 4% of the drug appears unchanged in the urine, and plasma half-life is about 4 hours. Diltiazem may reach saturation kinetics after single doses of greater than 60 mg. For these reasons, it is desirable to provide a one to two per day controlled release form of diltiazem hydrochloride. Diltiazem side effects include hypotension, itching, burning, flushing, arrythmia, and atrail flutter. Diltiazem forms a solid dispersion with Vitamin E TPGS.
3. Drug Formulations.
Once pharmacologic activity for a drug compound becomes known, the next objectives are to design drug product systems and/or devices that will effectively and efficiently deliver the compound to its active site. Moreover, after a system is developed and used, skilled drug formulators will often seek to improve or completely re-design it with the goal of optimizing drug delivery.
Broadly speaking, drug delivery systems include those that deliver the active drug compound by topical, aerosol, oral, injectable or rectal means. The oral dosage forms include tablets, capsules, gel capsules, syrups, suspensions, emulsions, micro-emulsions, pre-emulsion concentrates, and similar systems.
The development of an oral dosage form for an active drug is often driven by solubility concerns. The drug formulation, i.e., the combining of the active drug compound together with other inactive compounds and ingredients, will affect the amount or concentration of the drug compound that gets to the active site over the course of a given time period. The composition of the drug formulation directly affects the solubilization of the drug compound in the gastrointestinal tract, and consequently the extent and rate of the absorption of the active drug compound into the blood stream. In addition, the therapeutic value of a drug is also affected by the rate in which the drug dose is released from the delivery system itself, which in turn affects the rate and extent of solubilization of the active compound in the gastrointestinal tract prior to absorption.
The formulation of an acceptable dosage form for the delivery of a drug compound to the active site in the human body is a complex process involving trial and error. The development of an oral formulation for an insoluble or poorly soluble drug often involves the designing of a system that will affect the pH of the micro-environment surrounding the drug form in the gastrointestinal tract after ingestion.
In particular, the formulation may contain disintegrants and/or other agents that work to increase or decrease the pH of the micro- environment, and thus enhance drug dissolution. In addition, the drug may also be granulated to reduce its particle size and/or increase the surface area that is exposed to the gastric fluid. The amount of exposed surface area will affect the rate of drug dissolution and thus the amount of active drug that will be absorbed by the patient.
With respect to drug compounds of very poor or limited solubility, like cyclosporine, skilled formulators have used co-solvents, surfactants or wetting agents to reduce the surface tension of the liquid environment of the gastric fluid in which the active drug is to be dissolved. These agents wet the active drug more quickly so that more of the drug is exposed to the gastric fluid in a shorter time, and may enhance its dissolution. Common types of surfactants and co-solvents that can be used include the cationic, anionic (e.g., sodium lauryl sulfate and gelatin), and nonionic (e.g., MYRG) types, as well as such co-solvents as the polyethylene glycols ("PEGs").
The role of the binder in the tablet drug form is to provide a tablet with sufficient hardness and integrity, but also must allow for sufficient disintegration and dissolution in the gastric environment. In this sense, a binder performs the opposite function of a disintegrant. The types of binders that can be used in drug formulations include gelatins of numerous grades, starches and starch derivatives (including corn starch, StaRx 1500, carboxymethylated starch), cellulose derivatives, polyvinylpyrollidones, Veegums, polyethylene glycols, sugars, e.g., sucrose and lactose, sodium alginate and waxes.
The fillers used to bulk up a drug tablet or other form also should not interfere with the tablet's dissolution. Numerous fillers include the starch derivatives, sugars (e.g., lactose and sucrose), sorbitol, mannitol, cellulose derivatives and their inorganic salts, corn starch, Starch 1500, calcium phosphate, and Avicel.
Likewise, lubricants aid in the machining of a drug tablet. Every tablet needs a lubricant so that it will be ejected from the machine die with minimum force. However, the lubricant also must not interfere with the dissolution of the tablet. Lubricants include waxes, fatty acids, sodium salts of fatty acids and stearates.
4. Controlled Release Drug Formulations.
Controlled release formulations employ means that allow less drug to be released into the gut over time, and thereby allow the body to see lower concentrations of drug per unit time. They can thereby provide continuous delivery of the drug for a predetermined period, with predictable and reproducible kinetics. The term "controlled release" also refers to systems that provide control over the movement of the dosage form through the gastrointestinal tract, or that deliver the drug to a specific area for either local or systemic effect. See, generally, Gupta and Robinson, TREATISE ON ORAL CONTROLLED-DRUG DELIVERY Text Ed. 1992!, Ch. 6, edited by Agis Kydonieus, Mancel Dekker, Inc. ISBN 0-8247-8519-3.
Generally, there are three categories of oral drug delivery systems: conventional or immediate, first order slow release, and zero order release. In the conventional dosage form, a large maximum/minimum plasma drug concentration (Cmax/Cmin) is typically observed due to a rapid absorption of the drug into the body, relative to the drug's therapeutic index, i.e., the ratio of the maximum drug concentration needed to produce and maintain a desirable pharmacological response. In the conventional systems, drug content is released into the gastrointestinal tract within a short period of time, and plasma drug levels peak at a given time, usually within a few hours after dosing. The design of conventional oral drug delivery systems, including the cyclosporine formulations of the prior art, is generally based on getting the fastest possible rate of drug dissolution, often at the risk of creating undesirable, dose related side effects.
The goal of a controlled release formulation is to improve the therapeutic value of the active drug component by reducing the ratio of the maximum and minimum plasma drug combination (Cmax/Cmin) while maintaining drug plasma levels within the therapeutic window. The controlled release form seeks to give a drug with sufficient frequency and dose so that the ratio Cmax/Cmin in plasma at steady state is less than the therapeutic index, and to maintain drug levels at constant effective concentrations. In principle, in order to keep a constant plasma drug level, the drug formulation should be designed to provide an input rate into the body that is or approaches zero order, although in vivo profiles rarely match zero order kinetics based on in vitro models. The dosage forms of the present invention can be constructed along zero order, first order, or conventional release systems.
The type of controlled release systems that involve continuous or controlled release of the active drug employ dissolution control, diffusion control, a combination of dissolution and diffusion control, ion-exchange resins, osmotically controlled devices, slow dissolving salts or complexes, and pH independent formulations. These systems include tablet or similar formulations impregnated with water insoluble waxes, such as fatty acids, carnuba wax, and bees wax, or polymers, such as polyethylene, polypropylene, methacrylates, silicones, and PVC. When gastric fluid penetrates the surface of a polymer-impregnated tablet, the drug dissolves and diffuses through the polymer network. Other systems in these categories employ the encapsulation or microencapsulation of the drug particles with a slowly dissolving material prior to tablet compression. See Gupta and Robinson, supra; EUDRAGIT brochure: "EUDRAGIT Powders for Direct Compression," Huls America Inc, Somerset, N.J.; and UNION CARBIDE brochure: "SENTRY POLYOX, Water-Soluble Resins, NF In Sustained-Release Oral Pharmaceutical Applications," Union Carbide, Danbury Conn. (1995).
Other controlled release formulations are comprised of hydrophillic systems wherein a preparation of hydrophilic polymers, such as hydroxy propyl methyl cellulose, methyl cellulose, sodium carboxy methyl cellulose, polyethylene oxide polymers, natural gums and starches, is dispersed together with the drug and other excipients. These hydrophillic systems work by the uptake of the gastric fluid by the polymer, which is followed by swelling, dissolution of the drug, and diffusion through the swollen complex. Alternatively, they may work by the swelling of the complex and then erosion or dissolution of the polymer complex. See Gupta and Robinson, supra.
Generally, controlled delivery of lipophilic drugs requires techniques different than those employed with hydrophilic drugs. Lipophilic drugs must be solubilized and are, preferably, released in a controlled fashion, whereas hydrophilic drugs tend naturally to increase the rate at which water absorption and drug diffusion occurs. Consequently, a hydrophilic drug form must be modified to slow down the delivery.
The present invention, however, does not depend on the lipophilicity or hydrophilicity of the drug component because it functions by gradual surface dissolution of liquid crystal structures. As discussed below, the Vitamin E TPGS component of formulations within the scope of the present invention serves not only to solubilize lipophilic drugs and to disperse hydrophilic drugs, but also establishes a viscous liquid crystal gel structure at the dosage form/water interface, at which the dosage form slowly erodes as it goes into solution. See e.g. FIG. 3!. Thus, controlled diffusion of both hydrophilic and lipophilic drugs formulated in accordance with the present invention can be achieved.
In general, the advantages of controlled release systems may include reduced dosing frequency, better patient convenience and compliance, reduced gastrointestinal side effects and/or toxic side effects, fewer fluctuating plasma drug levels, more uniform drug effect, and lesser total dose.
It is particularly desirable to employ a controlled release system for cyclosporine as an alternative to the immediate release cyclosporine drug products of the prior art, e.g., NEORAL and SANDIMMUNE. The prior art cyclosporine products can result in toxic side effects, including nephrotoxic effects, due to the rapid release and absorption of high blood concentrations of the drug. See PHYSICIAN'S DESK REFERENCE, 51.sup.st Ed. (1997), p. 2405 (black box warning). Nephrotoxicity is believed to be a serious side effect caused by cyclosporine, and is dose related. When the dose is reduced, or another immunosuppressive agent is substituted, renal function improves. See e.g., Valantine H A, Shroeder I S, N. Engl. J. Med. 1995; 333: 660-661.
In an effort to reduce the nephrotoxic risks associated with cyclosporine therapy, prior art investigators have co-administered the drug with an agent that delays the metabolism of cyclosporine, effectively extending the half life and reducing the dose required to maintain therapeutic blood levels. However, this invention seeks to achieve these goals by providing a novel controlled release drug delivery system that does not require the co-administration of other agents. The present invention can control and reduce the release of cyclosporine per unit time, making it less than that of the immediate release formulation of the prior art. Thus, the present invention, unlike the prior art, does not overload the kidneys with immediate high levels of cyclosporine, thereby reducing the risks of nephrotoxicity.
5. Vitamin E TPGS.
In recent years, Vitamin E TPGS, or d-.alpha.-tocopheryl polyethylene glycol 1000 succinate, has been used as one of many excipients in complex immediate release drug formulations, usually emulsions or micro-emulsions, wherein the active drug compound is poorly soluble in water.
Vitamin E TPGS is a water soluble derivative of natural source Vitamin E, and has a dual nature, similar to an amphiphile, of hydrophilicity and lipophilicity. TPGS is also believed to be a bioavailability enhancer when co-administered with some lipophilic drugs, including cyclosporine.
The structure of the principal component of TPGS is: ##STR4##
Vitamin E TPGS is miscible in water and forms solutions with water at concentrations up to approximately 20% wt, beyond which liquid crystalline phases may form. It has a melting point of about 38.degree. to 41.degree. C. (100.degree. to 106.degree. F.). See, generally, "Eastman Vitamin E TPGS" Eastman Brochure, Eastman Chemical Co., Kingsport, Tenn. (October 1996). It has a relatively high crystallinity, high degradation temperature, and good thermal stability.
TPGS forms liquid crystalline phases in water. Micelles are formed at 0.02 percent weight. When TPGS concentration is above 20 percent weight, higher-viscosity liquid crystalline phases start to form. With increasing TPGS concentration in water, more complex liquid crystalline phases evolve, e.g., from isotropic globular micellar, to isotropic cylindrical micellar and hexagonal, hexagonal, mixed hexagonal and reversed hexagonal, reversed globular micellar, and to the lamellar phase. See "Eastman Vitamin E TPGS" Eastman Brochure, Eastman Chemical Co., Kingsport, Tenn. (October 1996).
TPGS is known as a surface active agent or as an emulsifier for use in complex formulations that include a number of other excipients that function as solvent, binder, and filler. However, the inventor herein knows of no examples wherein TPGS is used as the only or major solvent in a drug formulation, or as the delivery vehicle for controlled release of drugs, performing all of the functions of solvent, surfactant, binder, filler, and liquid crystal gel former. The Eastman Brochure, supra, suggests the blending of TPGS with water and a lipophilic drug to form an oil in water emulsion, but does not teach or suggest the direct melt blending, or solvent evaporation, of a lipophilic drug, such as cyclosporine, or dispersion of hydrophilic drugs, e.g., Diltiazem.HCl Salt, and TPGS, to form a solid solution or dispersion of drug and TPGS. (See Hawley's Condensed Chemical Dictionary (1987) for a definition of "dispersion"). Nor does the prior art teach or suggest the dry blending or mechanical mixing and compression of a solid solution of drug and Vitamin E TPGS for tablets, capsules or powder forms of drug/TPGS formulations where the drug is in a true Vitamin E TPGS solution, or solid dispersion, as opposed to an emulsion. The prior art also fails to disclose or teach the art of controlling the release or dissolution of the active drug form through the use of TPGS liquid crystal formation. Nor does the prior art teach the controlled dissolution at the surface of an oral dosage form, using liquid crystal formation of TPGS with water as the control mechanism.